Project Summary Although epithelial ovarian cancer (EOC) is initially a chemosensitive disease, it is infrequently cured by standard-of-care (SOC) platinum-based chemotherapy. Given the abundant evidence indicating that ovarian tumors are immunogenic, several immunotherapy approaches have been previously evaluated in this disease but without evidence of potent anti-tumor immunity or clinical activity. Immune checkpoint blockade (CPB) therapy, which has revolutionized treatment of multiple cancers, has demonstrated only modest effectiveness in EOC, highlighting the urgent need of new strategies to extend the benefit of CPB in this disease. Over recent years, we have developed new computational tools to identify immunogenic candidate patient-specific mutated epitopes (also called neoantigens) that are capable of stimulating tumor-specific T cell responses. Advances in prediction algorithms generated by our team now provide opportunities for studying the feasibility of generating neoantigen vaccines in tumors with intermediate mutation load (Abelin Immunity 2017), such as EOC, and for the testing of how the vaccine can be administered in conjunction with SOC therapy. This promising activity has led us to prospectively test the targeting of personal neopeptides as cancer vaccines, and we have demonstrated the safety, feasibility and immunologic activity of immunizing patients with advanced melanoma (Ott, Nature 2017) and glioblastoma (Keskin, Nature 2019) with personal vaccines consisting of up to 20 mutated epitopes per patient, delivered as synthetic long peptides (20-30mers) admixed with the potent immune adjuvant poly- ICLC, a TLR3 agonist (called ?Neovax?). In these proof-of-concept studies, some of the induced neoantigen- specific T cell responses could recognize autologous tumor cells. Moreover, complete responses with sustained remissions were observed in patients when anti-PD1 therapy was administered in addition to neoantigen vaccine. Based on these promising results, we now propose to evaluate, in a new clinical trial, the combined administration of personal neoantigen-targeted cancer vaccines together with CPB therapy for low residual volume EOC. We hypothesize that this approach will effectively expand existing tumor-reactive T-cells and broaden the T-cell repertoire to include new tumor-specific T-cells and thereby generating highly specific anti- tumor immunity with fewer autoimmune side effects. We will evaluate the feasibility and safety of Neovax in combination with nivolumab in EOC (Aim 1). Through integrated characterization of circulating blood immune responses with in situ changes in the tumor and tumor-infiltrating immune cells at serial time points across the course of therapy, including in the event of disease progression, we seek to elucidate candidate mechanisms of response and non-response to vaccine and CPB therapy (Aims 2 and 3).